The candidate, Ashley Walker Ph.D., is a vascular physiologist in the Department of Internal Medicine at the University of Utah. Dr. Walker's research focuses on the mechanisms mediating arterial aging with a specific focus on cerebral artery function. Her long term goal is to direct an independent extramurally- funded research laboratory who can integratively study vascular aging at the gene, cellular, tissue and systemic (whole-body) levels. The proposed K01 award will provide Dr. Walker with the necessary protected time for career development to achieve this goal. Career Development Plan. This award will support the further career development of Dr. Walker, allowing her to complete a well-rounded training plan in aging, vascular biology, and genetics. The career development plan will follow several separate but coordinated efforts to enhance the expertise of the applicant including training in new experimental techniques related to endothelial function and telomere biology; didactic course work designed to facilitate a better understanding of molecular genetics, biostatistics and gerontology; and attendance at regular aging, cardiovascular, and molecular medicine seminar series as well as other formal meetings within the university and nationally. Environment. The University of Utah is an ideal environment for Dr. Walker's career devolvement. This environment will allow for collaboration with renowned experts in aging, endothelial biology, and genetics, as well as opportunities for formal and informal training in areas related to vascular aging and general career development. Research. The aim of the research project is to examine novel mechanisms underlying impaired cerebral artery function with aging. We hypothesize that age-related increases in arterial stiffness lead to telomere dysfunction in the endothelial cells of cerebral resistance arteries. We further hypothesize that this telomere dysfunction, characterized by telomere uncapping, stimulates cell senescence and increased inflammatory signaling, ultimately resulting in endothelial dysfunction. We will address these hypotheses by studying animal and endothelial cell culture models of aging, isolated large artery stiffening, and endothelial cell telomere uncapping. The knowledge gained from the results of these studies could identify novel pharmaceutical targets for the prevention/treatment of age-related cerebral artery dysfunction. This is a worthwhile and relevant goal given the prevalence of cerebrovascular disease among older adults and the associated morbidity, mortality, and health care burden.